This proposal is a renewal application of the revised R01 grant funded for two years under the NIH American Recovery Reinvestment Act (ARRA). This grant, funded from July 15, 2009 to June 30, 2011, has led to elucidation of a series of fundamental principles concerning the role of IL-15 in EE pathogenesis. This renewal application seeks to extend our basic and translational analysis of EE, aimed at uncovering the role of IL-15 and IL-15-responsive cells in the regulation of esophageal eosinophilia in human EE. In the first cycle of this two-year R01 grant, we identified several key molecules that are directly responsible for the initiation and progression of EE pathogenesis in experimental models and have developed evidence that these findings apply to human EE. The details of our findings are presented in the progress report. In brief, we have demonstrated induced IL-15 mRNA/protein and iNKT cells in the esophageal biopsies of human EE and provided evidence that IL-15 and iNKT cells have a critical role in the initiation and progression of aeroallergen- o food allergen (peanut)-induced experimental EE. Therefore, in the extended cycle of grant tenure, we propose to test the central hypothesis that chronic IL-15 expression leads to the development of IgE- associated EE pathogenesis and that receptors, chemokines, and surface molecules of IL-15- responsive cells are the potential diagnostic and therapeutic targets molecules for human EE. The three specific aims will test our central hypothesis. In the first aim, we will test several sub-hypotheses concerning the role of IL-15 in the induction of mast cells; B cell growth, activation, and proliferation; and the mechanism of Ig class switching in EE by examining the esophageal transcript profile of IL-15 overexpression mice. Correlation of IL-15 with the presence of esophageal furrows, rings, and stricture in human EE will also be examined. The second aim will test the hypothesis that IL-15 and cell surface molecules and chemokines of IL-15-responsive cells may be novel diagnostic biomarkers for human EE. We will test several related sub- hypotheses concerning the mRNA and protein levels of IL-15, IL-15R, IgE, CD1d, V24, and CXCL16 in the blood of normal individuals and patients with gastroesophageal reflux disease (GERD) and EE. In the third aim, we propose a set of experiments designed to test several related primary hypotheses focused around iNKT cells and IL-15 being novel target molecules for EE therapy. Our studies are timely given the recent attention that EE is receiving in the medical community.